EP1287818B1 - Methods of antibiotic coating of objects having interconnected microcavities and the uses thereof - Google Patents
Methods of antibiotic coating of objects having interconnected microcavities and the uses thereof Download PDFInfo
- Publication number
- EP1287818B1 EP1287818B1 EP20020018322 EP02018322A EP1287818B1 EP 1287818 B1 EP1287818 B1 EP 1287818B1 EP 20020018322 EP20020018322 EP 20020018322 EP 02018322 A EP02018322 A EP 02018322A EP 1287818 B1 EP1287818 B1 EP 1287818B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- gentamicin
- microcavities
- hydrochloride
- process according
- sulphate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 230000003115 biocidal effect Effects 0.000 title claims description 35
- 238000000034 method Methods 0.000 title claims description 24
- 238000000576 coating method Methods 0.000 title claims description 16
- 239000011248 coating agent Substances 0.000 title claims description 12
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 claims description 62
- 229930182566 Gentamicin Natural products 0.000 claims description 57
- 229960002518 gentamicin Drugs 0.000 claims description 56
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 239000003242 anti bacterial agent Substances 0.000 claims description 16
- 229940088710 antibiotic agent Drugs 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 12
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 12
- 238000001704 evaporation Methods 0.000 claims description 11
- 230000008020 evaporation Effects 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 10
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 claims description 9
- 229920000728 polyester Polymers 0.000 claims description 9
- KOFBVFFPLADGGO-DUSUDKPKSA-N (3r,4s,5r,6r)-6-[(1r,2r)-1-amino-2-hydroxypropyl]oxane-2,3,4,5-tetrol Chemical compound C[C@@H](O)[C@@H](N)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O KOFBVFFPLADGGO-DUSUDKPKSA-N 0.000 claims description 8
- 102000008186 Collagen Human genes 0.000 claims description 8
- 108010035532 Collagen Proteins 0.000 claims description 8
- 229920001436 collagen Polymers 0.000 claims description 8
- 239000007943 implant Substances 0.000 claims description 8
- 229960002227 clindamycin Drugs 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 6
- 239000001506 calcium phosphate Substances 0.000 claims description 6
- 229920000159 gelatin Polymers 0.000 claims description 6
- 235000019322 gelatine Nutrition 0.000 claims description 6
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 6
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 6
- 239000011148 porous material Substances 0.000 claims description 6
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 6
- 229940078499 tricalcium phosphate Drugs 0.000 claims description 6
- 229910000391 tricalcium phosphate Inorganic materials 0.000 claims description 6
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 claims description 5
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 claims description 5
- 239000004100 Oxytetracycline Substances 0.000 claims description 5
- 239000004098 Tetracycline Substances 0.000 claims description 5
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Natural products C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 claims description 5
- CYDMQBQPVICBEU-XRNKAMNCSA-N chlortetracycline Chemical compound C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-XRNKAMNCSA-N 0.000 claims description 5
- GJPICBWGIJYLCB-UHFFFAOYSA-N dodecyl phenylmethanesulfonate Chemical compound CCCCCCCCCCCCOS(=O)(=O)CC1=CC=CC=C1 GJPICBWGIJYLCB-UHFFFAOYSA-N 0.000 claims description 5
- 229960003722 doxycycline Drugs 0.000 claims description 5
- 239000004744 fabric Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229960000625 oxytetracycline Drugs 0.000 claims description 5
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 claims description 5
- 235000019366 oxytetracycline Nutrition 0.000 claims description 5
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 claims description 5
- 229960002180 tetracycline Drugs 0.000 claims description 5
- 229930101283 tetracycline Natural products 0.000 claims description 5
- 235000019364 tetracycline Nutrition 0.000 claims description 5
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 claims description 4
- 239000011521 glass Substances 0.000 claims description 4
- 229960004023 minocycline Drugs 0.000 claims description 4
- 238000000465 moulding Methods 0.000 claims description 4
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 claims description 4
- HMEYVGGHISAPJR-IAHYZSEUSA-N rolitetracycline Chemical compound O=C([C@@]1(O)C(O)=C2[C@@H]([C@](C3=CC=CC(O)=C3C2=O)(C)O)C[C@H]1[C@@H](C=1O)N(C)C)C=1C(=O)NCN1CCCC1 HMEYVGGHISAPJR-IAHYZSEUSA-N 0.000 claims description 4
- 229960005009 rolitetracycline Drugs 0.000 claims description 4
- 238000005507 spraying Methods 0.000 claims description 4
- 150000003522 tetracyclines Chemical class 0.000 claims description 4
- 108010010803 Gelatin Proteins 0.000 claims description 3
- 229910001069 Ti alloy Inorganic materials 0.000 claims description 3
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 3
- 239000008273 gelatin Substances 0.000 claims description 3
- 235000011852 gelatine desserts Nutrition 0.000 claims description 3
- 239000004745 nonwoven fabric Substances 0.000 claims description 3
- 239000010935 stainless steel Substances 0.000 claims description 3
- 229910001220 stainless steel Inorganic materials 0.000 claims description 3
- 229910052719 titanium Inorganic materials 0.000 claims description 3
- 239000010936 titanium Substances 0.000 claims description 3
- OAPVUSSHCBRCOL-KBHRXELFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O OAPVUSSHCBRCOL-KBHRXELFSA-N 0.000 claims description 2
- NAUHPSRFNVHVLD-GGLKHSNMSA-N (4s,4as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-n-(pyrrolidin-1-ylmethyl)-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;hydrochloride Chemical compound Cl.OC([C@@]1(O)C(=O)C=2C([C@](C3=CC=CC(O)=C3C=2O)(C)O)C[C@H]1[C@@H](C1=O)N(C)C)=C1C(=O)NCN1CCCC1 NAUHPSRFNVHVLD-GGLKHSNMSA-N 0.000 claims description 2
- WTJXVDPDEQKTCV-UHFFFAOYSA-N 4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydron;chloride Chemical compound Cl.C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2C1CC1C(N(C)C)C(=O)C(C(N)=O)=C(O)C1(O)C2=O WTJXVDPDEQKTCV-UHFFFAOYSA-N 0.000 claims description 2
- PTNZGHXUZDHMIQ-UHFFFAOYSA-N 4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2C(C)C(C(O)C3C(C(O)=C(C(N)=O)C(=O)C3N(C)C)(O)C3=O)C3=C(O)C2=C1O PTNZGHXUZDHMIQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- XMEVHPAGJVLHIG-FMZCEJRJSA-N chembl454950 Chemical compound [Cl-].C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H]([NH+](C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O XMEVHPAGJVLHIG-FMZCEJRJSA-N 0.000 claims description 2
- 229960001229 ciprofloxacin hydrochloride Drugs 0.000 claims description 2
- DIOIOSKKIYDRIQ-UHFFFAOYSA-N ciprofloxacin hydrochloride Chemical compound Cl.C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 DIOIOSKKIYDRIQ-UHFFFAOYSA-N 0.000 claims description 2
- 229960001200 clindamycin hydrochloride Drugs 0.000 claims description 2
- 229960004082 doxycycline hydrochloride Drugs 0.000 claims description 2
- 229960002421 minocycline hydrochloride Drugs 0.000 claims description 2
- 229960005112 moxifloxacin hydrochloride Drugs 0.000 claims description 2
- IDIIJJHBXUESQI-DFIJPDEKSA-N moxifloxacin hydrochloride Chemical compound Cl.COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 IDIIJJHBXUESQI-DFIJPDEKSA-N 0.000 claims description 2
- 229960004368 oxytetracycline hydrochloride Drugs 0.000 claims description 2
- 229940072172 tetracycline antibiotic Drugs 0.000 claims description 2
- 229960004989 tetracycline hydrochloride Drugs 0.000 claims description 2
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 claims description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims 6
- 235000010216 calcium carbonate Nutrition 0.000 claims 4
- 239000001175 calcium sulphate Substances 0.000 claims 4
- 235000011132 calcium sulphate Nutrition 0.000 claims 4
- XIYOPDCBBDCGOE-IWVLMIASSA-N (4s,4ar,5s,5ar,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methylidene-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C=C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1[C@H](O)[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O XIYOPDCBBDCGOE-IWVLMIASSA-N 0.000 claims 3
- 239000001828 Gelatine Substances 0.000 claims 3
- 229960003405 ciprofloxacin Drugs 0.000 claims 3
- 229940042016 methacycline Drugs 0.000 claims 3
- 229960003702 moxifloxacin Drugs 0.000 claims 3
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 claims 3
- 238000009834 vaporization Methods 0.000 claims 3
- 230000008016 vaporization Effects 0.000 claims 3
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims 2
- 238000007654 immersion Methods 0.000 claims 2
- RDEIXVOBVLKYNT-HDZPSJEVSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-[(1r)-1-aminoethyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;(2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2 Chemical compound OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@H](O2)[C@@H](C)N)N)[C@@H](N)C[C@H]1N.O1[C@H]([C@@H](C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N RDEIXVOBVLKYNT-HDZPSJEVSA-N 0.000 claims 1
- NZKFUBQRAWPZJP-BXKLGIMVSA-N (2s,3r,4s,5s,6r)-4-amino-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,5s,6r)-3-amino-6-(aminomethyl)-5-hydroxyoxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-6-(hydroxymethyl)oxane-3,5-diol;sulfuric acid Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N.N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NZKFUBQRAWPZJP-BXKLGIMVSA-N 0.000 claims 1
- VXPSARQTYDZXAO-CCHMMTNSSA-N (4s,4ar,5s,5ar,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methylidene-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;hydron;chloride Chemical compound Cl.C=C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1[C@H](O)[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O VXPSARQTYDZXAO-CCHMMTNSSA-N 0.000 claims 1
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- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Chemical class CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- IYLGOENUAIGTQA-UHFFFAOYSA-O 3-hydroxy-2-phenylchromenylium Chemical compound OC1=CC2=CC=CC=C2[O+]=C1C1=CC=CC=C1 IYLGOENUAIGTQA-UHFFFAOYSA-O 0.000 description 1
- SATIISJKSAELDC-ZIOPZPSVSA-N 3-hydroxy-N-[(3R,6S,7R,10S,13S,16S,22R,24R)-24-hydroxy-7,11,13,17,20-pentamethyl-16-[(2S)-3-methylbutan-2-yl]-3-(2-methylpropyl)-2,5,9,12,15,18,21-heptaoxo-10-phenyl-8-oxa-1,4,11,14,17,20-hexazabicyclo[20.3.0]pentacosan-6-yl]pyridine-2-carboxamide Chemical compound CC(C)C[C@H]1NC(=O)[C@@H](NC(=O)c2ncccc2O)[C@@H](C)OC(=O)[C@@H](N(C)C(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)C(C)C)N(C)C(=O)CN(C)C(=O)[C@H]2C[C@@H](O)CN2C1=O)c1ccccc1 SATIISJKSAELDC-ZIOPZPSVSA-N 0.000 description 1
- YWMSSKBMOFPBDM-UHFFFAOYSA-N 4-carbamoylbenzenesulfonyl chloride Chemical compound NC(=O)C1=CC=C(S(Cl)(=O)=O)C=C1 YWMSSKBMOFPBDM-UHFFFAOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical class OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Chemical class CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
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- 239000004099 Chlortetracycline Substances 0.000 description 1
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- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Chemical class CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
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- 238000009792 diffusion process Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229930003949 flavanone Natural products 0.000 description 1
- 150000002208 flavanones Chemical class 0.000 description 1
- 235000011981 flavanones Nutrition 0.000 description 1
- 229930003944 flavone Chemical class 0.000 description 1
- 150000002213 flavones Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- HVQAJTFOCKOKIN-UHFFFAOYSA-N flavonol Chemical class O1C2=CC=CC=C2C(=O)C(O)=C1C1=CC=CC=C1 HVQAJTFOCKOKIN-UHFFFAOYSA-N 0.000 description 1
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- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Chemical class CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- OOYGSFOGFJDDHP-KMCOLRRFSA-N kanamycin A sulfate Chemical compound OS(O)(=O)=O.O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N OOYGSFOGFJDDHP-KMCOLRRFSA-N 0.000 description 1
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- XMKLKZFSQXZUQU-UHFFFAOYSA-N neoviridogrisein-II Natural products CC1OC(=O)C(C=2C=CC=CC=2)N(C)C(=O)C(C)NC(=O)C(C(C)C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(CC(C)C)NC(=O)C1NC(=O)C1=NC=CC=C1O XMKLKZFSQXZUQU-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical class CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
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- 239000010452 phosphate Substances 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/56—Porous materials, e.g. foams or sponges
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
- A61L2300/406—Antibiotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/606—Coatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
- A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/249921—Web or sheet containing structurally defined element or component
- Y10T428/249953—Composite having voids in a component [e.g., porous, cellular, etc.]
Definitions
- the present invention relates to a process for the antibiotic coating of bodies with interconnecting microcavities, so coated bodies and their use.
- Bone defects are relatively common in human and veterinary medicine and are particularly caused by bone fistulas, debris fractures and tumors. In case of open debris fractures, infections of the bone tissue are frequently observed. Bone defects can be treated by filling with suitable implants. In recent years, in particular porous implants have found interest, which have an osteoconductive effect due to their chemical composition and their porosity and promote ingrowth of the surrounding bone tissue. The treatment of bone defects is always problematic if additional microbial infections of the bone tissue are present. Bone tissue infections can be controlled by systemic or local application of appropriate antibiotics. The systemic use of antibiotics is problematic due to the sometimes not inconsiderable toxicity of the antibiotics.
- the local application directly in or on the infected tissue offers the advantage that high local antibiotic concentrations can be achieved while avoiding damaging antibiotic concentrations in the rest of the organism.
- These high local antibiotic concentrations at the site of the bacterial infection almost complete killing of the microorganisms is possible, so that the bacterial infections are treated very effectively.
- Soft tissue defects with bacterial infections are also frequently found in human and veterinary medicine. For the treatment of these infections, therefore, the local antibiotic treatment is of interest.
- slightly soluble salts of aminoglycoside antibiotics have received relatively little attention in water for the preparation of depot preparations and antibiotically active implants.
- slightly soluble salts known.
- gentamicin the preparation of slightly soluble salts based on higher fatty acids and arylalkylcarboxylic acids has been published (GM Luedemann, MJ Weinstein: Gentamycin and method of production, 16.07.1962, US 3,091,572 ).
- Examples of these are gentamicin salts of lauric acid, stearic acid, palmitic acid, oleic acid, phenylbutyric acid, naphthalene-1-carboxylic acid.
- gentamicin pentakis dodecyl sulfate for the preparation of injectables, ointments and creams. Further uses of gentamicin pentakis dodecyl sulfate solutions have not been considered.
- Stead acid salts and aliphatic sulfates of gentamicin and of etamycin were synthesized from the free base or from their salts in water at 50 to 80 ° C (H. Voege, P. Stadler, HJ Zeiler, S. Samaan, KG Metzger: Sparingly soluble salts of Aminoglycosides and formulations containing them with delayed release of active ingredient, 28.12.1982, DE 32 48 328 ).
- antibiotic fatty acid salts should be suitable as injection preparations.
- a recent development is poorly soluble aminoglycoside flavonoid phosphates (H. Wahlig, E. Dingeldein, R. Kirchlechner, D. Orth, W. Rogalski: flavonoid phosphate salts of aminoglycoside antibiotics. 13.10.1986, US 4,617,293 ).
- the salts of phosphoric acid monoesters of derivatives of hydroxyflavans, hydroxyflavens, hydroxyflavanones, hydroxyflavones and hydroxyflavylium are described. Particularly preferred are the derivatives of flavanones and flavones.
- These sparingly soluble salts are to be used as depot preparations.
- these salts are incorporated into collagen nonwovens (H. Wahlig, E. Dingeldein, D. Braun: Medicinally useful, shaped mass of collagen resorbable in the body., 22.09.1981, US 4,291,013 ).
- An example of this is the method described by Cimbollek and Nies for the solution of a gentamicin salt which is sparingly soluble in water and their use for coating (M. Cimbollek, B. Nies: Solvent for a sparingly soluble gentamicin salt. 04.05.1994, US 5,679,646 ).
- This gentamicin salt was synthesized based on 3-p-methoxybenzylidene-6-hydroxy-4'-methoxyflavanone-6-phosphate.
- These antibiotic-equipped bodies with interconnecting micro-cavities are to be used as implants for the treatment of bone and soft tissue defects in human and veterinary medicine.
- antibiotic coatings are to be produced, which allow an antibiotic release over a period of several days.
- the antibiotic coating should adhere well to the interior surface of bodies with interconnecting microvoids and must not occlude the intralinking microvoids.
- the invention is based on the surprising finding that antimicrobial coatings with sustained-release release are formed in the microvoids of bodies with interconnecting microvoids, in particular in that a solution of gentamicin pentakis dodecyl sulfate or of gentamicin pentakis dodecylsulfonate in a suitable organic solvent is introduced into the microvoids Solvent - for example, from the group of alcohols - is introduced by suitable means such as dipping, spraying or dripping, and after removal (such as by evaporation or evaporation) of the organic solvent, a layer of gentamicin pentakis dodecyl sulfate or of gentamicin pentakis dodecylsulfonat remains on the surface of the micro-cavities.
- the micro-cavities may be formed as pores.
- the bodies can be of organic or inorganic nature or also called composites of inorganic and organic material. They are constructed, for example, from collagen, gelatin, polyesters, titanium, titanium alloys, stainless steel, calcium carbonate, calcium sulfate, tricalcium phosphate or hydroxylapatite.
- Metallic bodies having interconnecting microcavities are understood in particular to be those which have microcavities which are joined to one another on their surface, and metallic bodies whose surface has been roughened by sandblasting in such a way that they have open interconnected cavities are also included. It is understood that the solutions used are as homogeneous as possible. Suitable solvents are, in particular, lower alcohols and also N, N-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO). Preferred solvents are methanol or ethanol.
- Gentamicin pentakis dodecyl sulfate, gentamicin tetrakis dodecyl sulfate Gentamicin tetrakis dodecyl sulfonate and also gentamicin pentakis dodecyl sulfonate are non-crystalline, waxy substances which show a certain course in the evaporation or in the evaporation of the organic solvent and thereby as a layer store on surfaces. Surprisingly, they adhere well to glass, ceramic and plastic surfaces.
- the production of antibiotic layers is only with the dissolved in methanol, ethanol, dimethyl sulfoxide and N, N-dimethylformamide dodecyl sulfates, dodecylsulfonates and dodecylbenzylsulfonates of the listed antibiotics without a gentamicin-containing antibiotic component.
- antibiotics may be mechanically fixed by inclusion or overlay in layers of gentamicin pentakis dodecyl sulfate or gentamicin tetrakis dodecyl sulfate and gentamicin pentakis dodecyl sulfonate or gentamicin tetrakis dodecyl sulfonate.
- an aqueous solution containing at least one water-soluble antibiotic component from the groups of the aminoglycoside antibiotics, the tetracycline antibiotics, the lincosamide antibiotics, and the 4-quinolone antibiotics is first included and subsequently, after evaporation and / or evaporation of the water, a solution consisting of gentamicin pentakis dodecyl sulfate and or gentamicin tetrakis dodecyl sulfate and or gentamicin pentakis dodecyl sulfonate and or gentamicin tetrakis dodecyl sulfonate and the solvent methanol or ethanol or dimethyl sulfoxide or N, N-dimethylformamide is introduced by dipping or spraying or drops.
- gentamicin sulfate clindamycin hydrochloride, clindamycin dihydrogen phosphate, Lincosamine hydrochloride, kanamycin sulfate, amikacin sulfate, tobramycin sulfate, tetracycline hydrochloride, chlortetracylin hydrochloride, oxytetracycline hydrochloride, demethylchlorotetracycline hydrochloride, methacyclin hydrochloride, doxycycline hydrochloride, rolitetracycline hydrochloride, minocycline hydrochloride and / or ciprofloxacin hydrochloride and / or moxifloxacin hydrochloride, preferably used.
- the invention also relates to a process for the antibiotic coating of bodies with interconnecting microcavities, in which one or more of the substances from the group Ciprofloxacindodecylbenzylsulfonat and / or Moxifloxacindodecylsulfat and / or Moxifloxacindodecylbenzylsulfonat and / or Moxifloxacindodecylsulfonat and / or the Dodecylsulfate and / or the Dodecylsulfonate of clindamycin, tetracycline, lincosamine, chlorotetracycline, oxytetracycline, demethylchlorotetracycline, methacyclin, doxycycline, Rolitetracyclins and the minocycin containing solution is introduced and after evaporation or evaporation of the solvent, a layer of these substances on the surface of the microvoids arises.
- nonwovens, felts, knitted or crocheted fabrics be coated from polyesters, collagen and gelatin.
- the respective dodecyl sulfate or sulfonate is preferably used in a concentration of 0.1 to 20.0 mass%, based on the solvent.
- porous shaped bodies of polyesters, calcium carbonate, calcium sulfate, tricalcium phosphate, hydroxyapatite and resorbable glass are coated.
- Gentamicin pentakis dodecyl sulfate was used for the examples, the production of which was carried out in accordance with the instructions of Jurado Soler et al. (A. Jurado Soler, JA Ortiz Hernandez, C. Ciuro Bertran: New gentamicin derivatives, process for their preparation and antibiotic composition containing them. 30.09.1974 DE 24 46 640 ). There were 135 mg or 270 mg gentamicin pentakis dodecylsulfat dissolved in 1 g of methanol. Into the pores of each cuboid phosphate glass, the previously prepared methanolic solution was added dropwise. The test specimens absorbed the solution and were then dried at room temperature to constant mass. Tab.
- Example 1 Compositions of the solutions used and the weight of the uncoated and coated specimens of Examples 1 and 2.
- Example no. Composition of the solution Mass of specimens before coating [Mg] Mass of the specimens after coating [Mg] Mass of the coating [Mg] 1 135 mg GPDS 1000 mg of methanol 3949 4087 130 2 270 mg GPDS 1000 mg of methanol 3992 4257 265 GPDS: Gentamicin pentakis dodecyl sulfate
- the molded articles prepared in Examples 1 and 2 were introduced into each 20 ml of physiological saline and stored therein at 37 ° C over a period of 28 days. Sampling took place after 1, 2, 3, 6, 9, 13, 15, 21 and 28 days of storage. After each sampling, the release medium was completely replaced with fresh medium.
- the antibiotic assay was performed using an agar diffusion assay of Bacillus subtilis ATCC 6633 as a test germ. The results are shown in Tab. Tab. 2: Results of the microbial determination of gentamicin release of the coated specimens of Examples 1 and 2 as a function of the storage time of the specimens in physiological saline at 37 ° C. Example no.
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Description
Die vorliegende Erfindung betrifft ein Verfahren zur antibiotischen Beschichtung von Körpern mit interkonnektierenden Mikrohohlräumen, so beschichtete Körper sowie deren Verwendung.The present invention relates to a process for the antibiotic coating of bodies with interconnecting microcavities, so coated bodies and their use.
Diese antibiotisch ausgerüsteten Körper mit interkonnektierenden Mikrohohlräumen sollen als Implantate in der Human- und Veterinärmedizin zur Behandlung von Knochendefekten und ggf. zur Behandlung von Weichteildefekten Verwendung finden. Dabei wird eine kontinuierliche Antibiotika-Freisetzung aus der auf der inneren Oberfläche der interkonnektierenden Mikrohöhlräume befindlichen antibiotischen Beschichtung über einen Zeitraum von mehreren Tagen angestrebt, damit eine mikrobielle Infektion im Bereich des zu behandelnden Knochendefekts und oder Weichteildefektes wirksam verhindert oder bekämpft werden kann.These antibiotically-treated bodies with interconnecting micro-cavities are to be used as implants in human and veterinary medicine for the treatment of bone defects and possibly for the treatment of soft-tissue defects. A continuous release of antibiotics from the antibiotic coating located on the inner surface of the interconnecting microfluidic cavities over a period of several days is sought so that a microbial infection in the area of the bone defect and or soft tissue defect to be treated can be effectively prevented or combated.
Knochendefekte treten in der Human- und Veterinärmedizin relativ häufig auf und werden insbesondere durch Knochenfisteln, Trümmerfrakturen und Tumoren verursacht. Bei offenen Trümmerfrakturen werden vielfach zusätzlich Infektionen des Knochengewebes beobachtet. Die Behandlung von Knochendefekten kann durch Auffüllung mit geeigneten Implantaten erfolgen. In den letzten Jahren haben insbesondere poröse Implantate Interesse gefunden, die aufgrund ihrer chemischen Zusammensetzung und ihrer Porosität eine osteokonduktive Wirkung aufweisen und ein Einwachsen des umgebenden Knochengewebes begünstigen. Problematisch ist die Behandlung von Knochendefekten immer dann, wenn zusätzlich mikrobielle Infektionen des Knochengewebes vorhanden sind. Infektionen des Knochengewebes können durch systemische oder lokale Applikation von geeigneten Antibiotika bekämpft werden. Die systemische Anwendung von Antibiotika ist aufgrund der mitunter nicht unbeträchtlichen Toxizität der Antibiotika problematisch. Die lokale Applikation direkt im oder am infizierten Gewebe bietet dagegen den Vorteil, dass hohe lokale Antibiotika-Konzentrationen erreicht werden können unter Vermeidung von schädigenden Antibiotika-Konzentrationen im übrigen Organismus. Durch diese hohen lokalen Antibiotika-Konzentrationen am Ort der bakteriellen Infektion ist eine fast vollständige Abtötung der Mikroorganismen möglich, so dass die bakteriellen Infektionen sehr wirksam behandelt werden. Besonders vorteilhaft ist es, wenn am Ort der bakteriellen Infektionen eine wirksame Antibiotikum-Konzentration über einen Zeitraum von mehreren Tagen bis Wochen aufrechterhalten wird, damit das Antibiotikum möglichst tief in das infizierte Gewebe eindringen kann und dadurch auch schwer zugängliche Keime vernichtet werden. Weichteildefekte mit bakteriellen Infektionen sind in der Human- und Veterinärmedizin ebenfalls häufig zu finden. Zur Behandlung dieser Infektionen ist daher auch die lokale Antibiotika-Behandlung von Interesse.Bone defects are relatively common in human and veterinary medicine and are particularly caused by bone fistulas, debris fractures and tumors. In case of open debris fractures, infections of the bone tissue are frequently observed. Bone defects can be treated by filling with suitable implants. In recent years, in particular porous implants have found interest, which have an osteoconductive effect due to their chemical composition and their porosity and promote ingrowth of the surrounding bone tissue. The treatment of bone defects is always problematic if additional microbial infections of the bone tissue are present. Bone tissue infections can be controlled by systemic or local application of appropriate antibiotics. The systemic use of antibiotics is problematic due to the sometimes not inconsiderable toxicity of the antibiotics. The local application directly in or on the infected tissue, on the other hand, offers the advantage that high local antibiotic concentrations can be achieved while avoiding damaging antibiotic concentrations in the rest of the organism. These high local antibiotic concentrations at the site of the bacterial infection almost complete killing of the microorganisms is possible, so that the bacterial infections are treated very effectively. It is particularly advantageous if an effective antibiotic concentration is maintained over a period of several days to weeks at the site of the bacterial infections, so that the antibiotic can penetrate as deeply as possible into the infected tissue and thereby even hard to reach germs are destroyed. Soft tissue defects with bacterial infections are also frequently found in human and veterinary medicine. For the treatment of these infections, therefore, the local antibiotic treatment is of interest.
Bisher fanden in Wasser gering lösliche Salze der Aminoglykosid-Antibiotika relativ wenig Beachtung für die Herstellung von Depotpräparaten und von antibiotisch wirksamen Implantaten. Es sind eine Reihe von geringlöslichen Salzen bekannt. So wurde beim Gentamicin die Darstellung geringlöslicher Salze basierend auf höheren Fettsäuren und Arylalkylcarbonsäuren publiziert (G. M. Luedemann, M. J. Weinstein: Gentamycin and method of production. 16.07.1962,
Die Erzeugung von einfachen Antibiotikum-/Antibiotka-Depots in den Porensystemen von porösen Körpern durch Tränken von porösen Körpern mit wässrigen Antibiotika-Lösungen ist allgemeiner Kenntnisstand (R. Reiner, W. Kißing, H. Döring, K. Köster, H. Heide: Implantierbares Pharmaka-Depot.
Zusammenfassend kann festgestellt werden, dass bisher keine Verfahren bekannt sind, bei denen antibiotische Beschichtungen auf der Oberfläche von interkonnektierenden Mikrohohlräumen aufgebracht werden, die aus in Wasser gering löslichen Salzen des Gentamicins bestehen, welche einen anionischen Rest aus der Gruppe der Alkylsulfate und oder Alkylsulfonate enthalten. Die Schichtbildungseigenschaften von in Wasser gering löslichen Antibiotika-Salzen auf Basis von organischen Sulfaten und Sulfonaten fanden bisher keine Beachtung.In summary, it can be stated that no methods are known in which antibiotic coatings are applied to the surface of interconnecting microcavities consisting of slightly water-soluble salts of gentamicin, which contain an anionic radical from the group of alkyl sulfates and / or alkyl sulfonates. The film-forming properties of water-insoluble antibiotic salts based on organic sulfates and sulfonates have so far received no attention.
Der vorliegenden Erfindung liegt die Aufgabe zugrunde, verbesserte Körper mit antibiotischer Beschichtung, sowie ein einfaches, kostengünstiges Herstellungsverfahren zur antibiotischen Beschichtung von Körpern mit interkonnektierenden Mikrohohlräumen zu entwickeln. Diese antibiotisch ausgerüsteten, Körper mit interkonnektierenden Mikrohohlräumen sollen als Implantate zur Behandlung von Knochen- und Weichteildefekten in der Human- und Veterinärmedizin Verwendung finden. Mit diesem Verfahren sollen in einfacher Weise, unter Verzicht auf polymere Bindemittel, antibiotische Beschichtungen erzeugt werden, die eine Antibiotika-Freisetzung über einen Zeitraum von mehreren Tagen ermöglichen. Die antibiotische Beschichtung soll auf der inneren Oberfläche von Körpern mit interkonnektierenden Mikrohohlräumen gut haften und darf die innterkonnektierenden Mikrohohlräume nicht verschließen.It is an object of the present invention to develop improved antibiotic coated bodies, as well as a simple, inexpensive manufacturing method for antibiotic coating of bodies with interconnecting microvoids. These antibiotic-equipped bodies with interconnecting micro-cavities are to be used as implants for the treatment of bone and soft tissue defects in human and veterinary medicine. With this method, in a simple manner, dispensing with polymeric binders, antibiotic coatings are to be produced, which allow an antibiotic release over a period of several days. The antibiotic coating should adhere well to the interior surface of bodies with interconnecting microvoids and must not occlude the intralinking microvoids.
Die Aufgabe wird durch die Merkmale der unabhängigen Ansprüche gelöst. Vorteilhafte Ausgestaltungen sind in den Unteransprüchen angegeben.The object is solved by the features of the independent claims. Advantageous embodiments are specified in the subclaims.
Der Erfindung liegt der überraschende Befund zugrunde, dass antibiotische Beschichtungen mit retardierender Wirkstofffreisetzung in den Mikrohohlräumen von Körpern mit interkonnektierenden Mikrohohlräumen insbesondere dadurch gebildet werden, dass in die Mikrohohlräume eine Lösung von Gentamicin-pentakis-dodecylsulfat oder von Gentamicin-pentakis-dodecylsulfonat in einem geeigneten organischen Lösungsmittel - beispielsweise aus der Gruppe der Alkohole - durch geeignete Maßnahmen wie Tauchen, Sprühen oder Tropfen, eingebracht wird und nach Entfernen (wie etwa durch Verdampfung oder Verdunstung) des organischen Lösungsmittels eine Schicht aus Gentamicin-pentakis-dodecylsulfat oder von Gentamicin-pentakis-dodecylsulfonat auf der Oberfläche der Mikrohohlräume zurückbleibt. Die Mikrohohlräume können als Poren ausgebildet sein.The invention is based on the surprising finding that antimicrobial coatings with sustained-release release are formed in the microvoids of bodies with interconnecting microvoids, in particular in that a solution of gentamicin pentakis dodecyl sulfate or of gentamicin pentakis dodecylsulfonate in a suitable organic solvent is introduced into the microvoids Solvent - for example, from the group of alcohols - is introduced by suitable means such as dipping, spraying or dripping, and after removal (such as by evaporation or evaporation) of the organic solvent, a layer of gentamicin pentakis dodecyl sulfate or of gentamicin pentakis dodecylsulfonat remains on the surface of the micro-cavities. The micro-cavities may be formed as pores.
Die Körper können organischer oder anorganischer Natur sein oder auch sogenannte Composites aus anorganischem und organischem Material. Sie sind z.B. aus Kollagen, Gelatine, Polyestern, Titan, Titanlegierungen, Edelstahl, Calciumcarbonat, Calciumsulfat, Tricalciumphosphat oder Hydroxylapatit aufgebaut. Unter metallischen Körpern mit interkonnektierenden Mikrohohlräumen werden insbesondere solche verstanden, die an ihrer Oberfläche Mikrohohlräume aufweisen, die miteinander verbunden sind, und es werden auch metallische Körper dazugerechnet, deren Oberfläche durch Sandstrahlen so aufgerauht wurde, dass sie offene, miteinander verbundene Hohlräume aufweisen. Es versteht sich, dass die benutzten Lösungen möglichst homogen sind. Als Lösungsmittel kommen vor allem niedere Alkohole sowie N,N-Dimethylformamid (DMF) oder Dimethylsulfoxid (DMSO) in Frage. Bevorzugte Lösungsmittel sind Methanol oder Ethanol.The bodies can be of organic or inorganic nature or also called composites of inorganic and organic material. They are constructed, for example, from collagen, gelatin, polyesters, titanium, titanium alloys, stainless steel, calcium carbonate, calcium sulfate, tricalcium phosphate or hydroxylapatite. Metallic bodies having interconnecting microcavities are understood in particular to be those which have microcavities which are joined to one another on their surface, and metallic bodies whose surface has been roughened by sandblasting in such a way that they have open interconnected cavities are also included. It is understood that the solutions used are as homogeneous as possible. Suitable solvents are, in particular, lower alcohols and also N, N-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO). Preferred solvents are methanol or ethanol.
Gentamicin-pentakis-dodecylsulfat, Gentamicin-tetrakis-dodecylsulfat Gentamicin-tetrakis-dodecylsulfonat und auch Gentamicin-pentakis-dodecylsulfonat sind nichtkristalline, wachsartige Substanzen, die bei der Abdampfung bzw. bei der Verdunstung des organischen Lösungsmittels einen gewissen Verlauf zeigen und sich dabei als Schicht auf Oberflächen auflagern. Sie haften überraschenderweise gut auf Glas-, Keramik- und Kunststoffoberflächen.Gentamicin pentakis dodecyl sulfate, gentamicin tetrakis dodecyl sulfate Gentamicin tetrakis dodecyl sulfonate and also gentamicin pentakis dodecyl sulfonate are non-crystalline, waxy substances which show a certain course in the evaporation or in the evaporation of the organic solvent and thereby as a layer store on surfaces. Surprisingly, they adhere well to glass, ceramic and plastic surfaces.
Überraschenderweise lösen sich auch Clindamycin-dodecylsulfat, Clindamycin-dodecylsulfonat, Lincosamin-dodecylsulfat, Lincosamin-dodecylsulfonat in Methanol, Ethanol Dimethylsulfoxid und N,N-Dimethylformamid. Diese Stoffe können somit ohne weiteres den Gantamicin-Lösungen zugefügt werden. Es ist auch möglich Tetracyclin-dodecylsulfat oder Tetracylindodecylsulfonat in den Lösungen einzusetzen. Man kann auch anstelle des Tetracyclindodecylsulfates die Dodecylsulfate und oder die Dodecylsulfonate des Chlortetracyclins, des Oxytetracylins, des Demethylchlortetracyclins, des Methacyclins, des Doxycyclins, des Rolitetracyclins und des Minocyclins verwenden. Es kann auch Coprofloxacindodecylbenzylsulfonat zugesetzt werden. Entsprechend entstehen an den Oberflächen der Mikrohohlräume Beschichtungen enthaltend die Gentamicinkomponenten und mindestens eine der genannten weiteren Antibiotika-Komponenten. Im Sinne der Erfindung ist auch die Herstellung von antibiotischen Schichten nur mit den in Methanol, Ethanol, Dimethylsulfoxid und N,N-Dimethylformamid gelösten Dodecylsulfaten, Dodecylsulfonaten und Dodecylbenzylsulfonaten der aufgeführten Antibiotika ohne eine Gentamicin enthaltende antibiotische Komponente.Surprisingly, clindamycin dodecylsulfate, clindamycin dodecylsulfonate, lincosamine dodecylsulfate, lincosamine dodecylsulfonate in methanol, ethanol, dimethylsulfoxide and N, N-dimethylformamide also dissolve. These substances can thus be readily added to the gantamicin solutions. It is also possible to use tetracycline-dodecylsulfate or tetracylindodecylsulfonate in the solutions. It is also possible to use, instead of the tetracycline dodecyl sulphate, the dodecyl sulphates and / or the dodecyl sulphonates of chlortetracycline, oxytetracycline, demethyl chlorotetracycline, methacacycline, doxycycline, rolitetracycline and minocycline. Coprofloxacindodecylbenzylsulfonate may also be added. Accordingly arise on the surfaces of the micro-cavities coatings containing the gentamicin and at least one of said other antibiotic components. For the purposes of the invention, the production of antibiotic layers is only with the dissolved in methanol, ethanol, dimethyl sulfoxide and N, N-dimethylformamide dodecyl sulfates, dodecylsulfonates and dodecylbenzylsulfonates of the listed antibiotics without a gentamicin-containing antibiotic component.
Überraschenderweise können in Schichten aus Gentamicin-pentakis-dodecylsulfat oder Gentamicin-tetrakis-dodecylsulfat und Gentamicin-pentakis-dodecylsulfonat oder Gentamicin-tetrakis-dodecylsulfonat andere Antibiotika durch Einschluss oder Überdeckung mechanisch fixiert werden. Es ist daher möglich, dass in interkonnektierende Mikrohohlräume von Körpern zuerst eine wässrige Lösung, die mindestens eine in Wasser leicht lösliche antibiotische Komponente aus den Gruppen der Aminoglykosid-Antibiotika, der Tetracyclin-Antibiotika, der Lincosamid-Antibiotika und der 4-Chinolon-Antibiotika enthält, und anschließend nach Verdampfung und oder Verdunstung des Wassers eine Lösung, die aus Gentamicin-pentakis-dodecylsulfat und oder Gentamicin-tetrakis-dodecylsulfat und oder Gentamicin-pentakis-dodecylsulfonat und oder Gentamicin-tetrakis-dodecylsulfonat und dem Lösungsmittel Methanol oder Ethanol oder Dimethylsulfoxid oder N,N-Dimethylformamid besteht, durch Tauchen oder Sprühen oder Tropfen eingebracht wird. Es entsteht im Ergebnis eine Doppelschicht. Bei der Anwendung in Implantaten wird dann das zweite Antibiotikum erst freigesetzt, wenn die Gentamicin-Schicht zumindest teilweise gelöst ist. Als in Wasser leicht lösliche antibiotische Komponente werden in dieser Ausführungsform der Erfindung Gentamicinsulfat, Clindamycinhydrochlorid, Clindamycindihydrogenphosphat, Lincosaminhydrochlorid, Kanamycinsulfat, Amikacinsulfat, Tobramycinsulfat, Tetracyclinhydrochlorid, Chlortetracylinhydrochlorid, Oxytetracyclinhydrochlorid, Demethylchlortetracyclin-hydrochlorid, Methacyclinhydrochlorid, Doxycyclinhydrochlorid, Rolitetracyclinhydrochlorid, Minocyclinhydrochlorid und oder Ciprofloxacinhydrochlorid und oder Moxifloxacinhydrochlorid, bevorzugt eingesetzt.Surprisingly, other antibiotics may be mechanically fixed by inclusion or overlay in layers of gentamicin pentakis dodecyl sulfate or gentamicin tetrakis dodecyl sulfate and gentamicin pentakis dodecyl sulfonate or gentamicin tetrakis dodecyl sulfonate. It is therefore possible that, in interconnecting microvoid bodies, an aqueous solution containing at least one water-soluble antibiotic component from the groups of the aminoglycoside antibiotics, the tetracycline antibiotics, the lincosamide antibiotics, and the 4-quinolone antibiotics is first included and subsequently, after evaporation and / or evaporation of the water, a solution consisting of gentamicin pentakis dodecyl sulfate and or gentamicin tetrakis dodecyl sulfate and or gentamicin pentakis dodecyl sulfonate and or gentamicin tetrakis dodecyl sulfonate and the solvent methanol or ethanol or dimethyl sulfoxide or N, N-dimethylformamide is introduced by dipping or spraying or drops. The result is a double layer. When used in implants, the second antibiotic is then released only when the gentamicin layer is at least partially dissolved. As a readily water-soluble antibiotic component in this embodiment of the invention gentamicin sulfate, clindamycin hydrochloride, clindamycin dihydrogen phosphate, Lincosamine hydrochloride, kanamycin sulfate, amikacin sulfate, tobramycin sulfate, tetracycline hydrochloride, chlortetracylin hydrochloride, oxytetracycline hydrochloride, demethylchlorotetracycline hydrochloride, methacyclin hydrochloride, doxycycline hydrochloride, rolitetracycline hydrochloride, minocycline hydrochloride and / or ciprofloxacin hydrochloride and / or moxifloxacin hydrochloride, preferably used.
Die Erfindung betrifft auch ein Verfahren zur antibiotischen Beschichtung von Körpern mit interkonnektierenden Mikrohohlräumen, bei dem in die Mikrohohlräume eine oder mehrere der Substanzen aus der Gruppe Ciprofloxacindodecylbenzylsulfonat und/oder Moxifloxacindodecylsulfat und/oder Moxifloxacindodecylbenzylsulfonat und/oder Moxifloxacindodecylsulfonat und/oder der Dodecylsulfate und/oder der Dodecylsulfonate des Clindamycins, des Tetracyclins, des Lincosamins, des Chlortetracyclins, des Oxytetracylins, des Demethylchlortetracyclins, des Methacyclins, des Doxycyclins, des Rolitetracyclins und des Minocyclins enthaltende Lösung eingebracht wird und nach Verdampfung oder Verdunstung des Lösungsmittels eine Schicht dieser Substanzen auf der Oberfläche der Mikrohohlräume entsteht.The invention also relates to a process for the antibiotic coating of bodies with interconnecting microcavities, in which one or more of the substances from the group Ciprofloxacindodecylbenzylsulfonat and / or Moxifloxacindodecylsulfat and / or Moxifloxacindodecylbenzylsulfonat and / or Moxifloxacindodecylsulfonat and / or the Dodecylsulfate and / or the Dodecylsulfonate of clindamycin, tetracycline, lincosamine, chlorotetracycline, oxytetracycline, demethylchlorotetracycline, methacyclin, doxycycline, Rolitetracyclins and the minocycin containing solution is introduced and after evaporation or evaporation of the solvent, a layer of these substances on the surface of the microvoids arises.
Erfindungsgemäß ist ferner, dass bevorzugt Vliese, Filze, Gewirke oder Gestricke aus Polyestern, Kollagen und Gelatine beschichtet werden.According to the invention, it is further preferred that nonwovens, felts, knitted or crocheted fabrics be coated from polyesters, collagen and gelatin.
Das jeweilige Dodecylsulfat oder -sulfonat wird bevorzugt in einer Konzentration von 0,1 bis 20,0 Masseprozent, bezogen auf das Lösungsmittel verwendet.The respective dodecyl sulfate or sulfonate is preferably used in a concentration of 0.1 to 20.0 mass%, based on the solvent.
Erfindungsgemäß ist auch, dass bevorzugt poröse Formkörper aus Polyestern, Calciumcarbonat, Calciumsulfat, Tricalciumphosphat, Hydroxylapatit und resorbierbaren Glas beschichtet werden.It is also according to the invention that preferably porous shaped bodies of polyesters, calcium carbonate, calcium sulfate, tricalcium phosphate, hydroxyapatite and resorbable glass are coated.
Im Sinne der Erfindung ist, dass die antibiotisch beschichteten Körper mit interkonnektierenden Mikrohohlräumen als Implantate verwendet werden.For the purposes of the invention, the antibiotically coated bodies with interconnecting microcavities are used as implants.
Die nachfolgenden Beispiele erklären die Erfindung ohne sie einzuschränken.The following examples explain the invention without restricting it.
Die Erfindung soll durch die nachstehenden Beispiele 1 und 2 erläutert werden.The invention will be illustrated by the following Examples 1 and 2.
Als Körper mit interkonnektierenden Mikrohohlräumen wurden quaderförmige, resorbierbare Phosphatgläser mit den Abmessungen von 20 x 20 x 10 mm für die Beispiele 1 und 2 verwendet. Sie hatten eine Gesamt-Porosität von 65 Volumenprozent.As a body with interconnecting microcavities cuboid resorbable phosphate glasses with the dimensions of 20 x 20 x 10 mm for Examples 1 and 2 were used. They had a total porosity of 65% by volume.
Für die Beispiele kam Gentamicin-pentakis-dodecylsulfat zur Anwendung, dessen Herstellung entsprechend der Vorschrift von Jurado Soler et al. (A. Jurado Soler, J. A. Ortiz Hernandez, C. Ciuro Bertran: Neue Gentamicinderivate, Verfahren zur Herstellung derselben und diese enthaltende antibiotisch wirksame Zusammensetzung.
[mg]
[mg]
[mg]
1000 mg Methanol
1000 mg Methanol
[Mg]
[Mg]
[Mg]
1000 mg of methanol
1000 mg of methanol
Die in den Beispielen 1 und 2 hergestellten Formkörper wurden in jeweils 20 ml physiologische Kochsalzlösung eingebracht und in dieser bei 37 °C über einen Zeitraum von 28 Tagen gelagert. Die Probennahme erfolgte nach 1, 2, 3, 6, 9, 13, 15, 21 und 28 Tagen Lagerungszeit. Nach jeder Probennahme wurde das Freisetzungsmedium vollständig durch frisches Medium, ersetzt. Die Antibiotika-Wertbestimmung wurde mit einem Agardiffusionstest unter Verwendung von Bacillus subtilis ATCC 6633 als Testkeim durchgeführt. Die Ergebnisse sind in Tab. 2 dargestellt.
[mg]
[Mg]
Claims (23)
- Process for the antibiotic coating of bodies with interconnecting microcavities, characterized in that a solution containing gentamicin dodecylsulphate having 1 to 5 dodecylsulphate groups per gentamicin molecule and/or gentamicin dodecylsulphonate having 1 to 5 dodecylsulphonate groups per gentamicin molecule is introduced into the microcavities and, after vaporization or evaporation of the solvent, a layer of gentamicin dodecylsulphate or gentamicin dodecylsulphonate forms on the surface of the microcavities - the solvent used being at least one organic solvent.
- Process according to Claim 1, characterized in that gentamicin pentakisdodecylsulphate and/or gentamicin tetrakisdodecylsulphate and/or gentamicin pentakisdodecylsulphonate and/or gentamicin tetrakisdodecylsulphonate is used.
- Process according to Claim 1, characterized in that one of the solvents is methanol, ethanol, N,N-dimethylformamide and dimethyl sulphoxide.
- Process according to any of Claims 1 to 3, characterized in that the introduction is effected by immersion or spraying or dripping of the solution.
- Process according to any of Claims 1 to 4, characterized in that the bodies are composed of collagen, gelatine or polyester, calcium carbonate, calcium sulphate, tricalcium phosphate or hydroxylapatite.
- Process according to any of Claims 1 to 5, characterized in that one or more of the substances from the group consisting of ciprofloxacin dodecylbenzylsulphonate and/or of the dodecylsulphates and/or of the dodecylsulphonates of clindamycin, of tetracycline, of lincosamine, of chlorotetracycline, of oxytetracycline, of demethylchlorotetracycline, of methacycline, of doxycycline, of rolitetracycline and of minocycline are additionally used in the solution.
- Process according to any of Claims 1 to 6, characterized in that first an aqueous solution which contains at least one freely water-soluble antibiotic component from the group consisting of the aminoglycoside antibiotics, of the tetracycline antibiotics, of the lincosamide antibiotics and of the 4-quinolone antibiotics and then, after vaporization and/or evaporation of the water, a solution of gentamicin dodecylsulphate or gentamicin dodecylsulphonate, in particular of gentamicin pentakisdodecylsulphate and/or gentamicin tetrakisdodecylsulphate and/or gentamicin pentakisdodecylsulphonate and/or gentamicin tetrakisdodecylsulphonate, in methanol, ethanol, N,N-dimethylformamide and/or dimethyl sulphoxide is introduced into the interconnecting microcavities by immersion or spraying or dripping.
- Process according to Claim 7, characterized in that gentamicin sulphate, clindamycin hydrochloride, clindamycin hydrogen phosphate, lincosamine hydrochloride, kanamycin sulphate, amikacin sulphate, tobramycin sulphate, tetracycline hydrochloride, chlorotetracycline hydrochloride, oxytetracycline hydrochloride, demethylchlorotetracycline hydrochloride, methacycline hydrochloride, doxycycline hydrochloride, rolitetracycline hydrochloride, minocycline hydrochloride and/or ciprofloxacin hydrochloride and/or moxifloxacin hydrochloride are used as freely water-soluble antibiotic component(s).
- Process according to any of Claims 1 to 8, characterized in that 0.1 to 20.0 percent by mass of the dodecyl sulphate or dodecyl sulphonate, based on the solvent, are used.
- Process according to any of Claims 1 to 9, characterized in that nonwovens, felts, knitted fabrics or continuously knitted fabrics of polyester, collagen or gelatine are antibiotically coated.
- Process according to any of Claims 1 to 9, characterized in that porous mouldings of polyesters, calcium carbonate, calcium sulphate, tricalcium phosphate, hydroxylapatite or resorbable glass are coated.
- Process according to any of Claims 1 to 9, characterized in that metallic mouldings of titanium, titanium alloys or stainless steel are coated.
- Process for the antibiotic coating of bodies with interconnecting microcavities, characterized in that solution containing one or more of the substances from the group consisting of ciprofloxacin dodecylbenzylsulphonate and/or moxifloxacin dodecylsulphate and/or moxifloxacin dodecylbenzylsulphonate and/or moxifloxacin dodecylsulphonate and/or of the dodecylsulphates and/or of the dodecylsulphonates of clindomycin, of tetracycline, of lincosamine, of chlorotetracycline, of oxytetracycline, of demethylchlorotetracycline, of methacycline, of doxycycline, of rolitetracycline and of minocycline is introduced into the microcavities and, after vaporization or evaporation of the solvent, a layer of these substances forms on the surface of the microcavities - the solvent used being at least one organic solvent.
- Process according to any of Claims 1 to 13, characterized in that the microcavities are in the form of pores.
- Body with interconnecting microcavities, characterized in that a layer which comprises gentamicin dodecylsulphate having 1 to 5 dodecylsulphate groups per gentamicin molecule or gentamicin dodecylsulphonate having 1 to 5 dodecylsulphonate groups per gentamicin molecule is formed on the surface of the microcavities.
- Body according to Claim 15, characterized in that the layer comprises gentamicin pentakisdodecylsulphate and/or gentamicin tetrakisdodecylsulphate or gentamicin pentakisdodecylsulphonate and/or gentamicin tetrakisdodecylsulphonate.
- Body with interconnecting microcavities, characterized in that a layer which comprises one or more of the substances from the group consisting of ciprofloxacin dodecylbenzylsulphonate and/or of the dodecylsulphates and/or of the dodecylsulphonates of clindamycin, of tetracycline, of lincosamine, of chlorotetracycline, of oxytetracycline of demethylchlorotetracycline, of methacycline, of doxycycline, of rolitetracycline and minocycline is formed on the surface of the microcavities.
- Body according to Claim 15 or 17, characterized in that it is formed from collagen, gelatin or polyester, calcium carbonate, calcium sulphate, tricalcium phosphate or hydroxylapatite.
- Body according to Claim 15 or 17, characterized in that it is in the form of a nonwoven, felt, continuously knitted fabric or knitted fabric of polyester, collagen or gelatine.
- Body according to Claim 15 or 17, characterized in that it is in the form of a porous moulding of polyester, calcium carbonate, calcium sulphate, tricalcium phosphate, hydroxylapatite or resorbable glass.
- Body according to Claim 15 or 17, characterized in that it is formed from titanium, titanium alloys or stainless steel.
- Body according to Claim 15 or 17, characterized in that the microcavities are in the form of pores.
- Use of bodies with interconnecting microcavities according to any of Claims 15 to 22 for the production of implants.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CY081100074T CY1107271T1 (en) | 2001-08-31 | 2008-01-18 | METHOD FOR ANTIBIOTIC BODY COATING WITH COMMUNICATED MICROWELLS, BODIES COATED IN THIS WAY AND USE THIS |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10142465A DE10142465A1 (en) | 2001-08-31 | 2001-08-31 | Production of an antibiotic coating on a porous body useful as an implant comprises impregnation with a solution of gentamicin dodecyl sulfate or sulfonate and evaporation of the solvent |
DE10142465 | 2001-08-31 | ||
DE10204307 | 2002-02-01 | ||
DE10204307 | 2002-02-01 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1287818A1 EP1287818A1 (en) | 2003-03-05 |
EP1287818B1 true EP1287818B1 (en) | 2007-11-21 |
Family
ID=26010028
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP20020018322 Expired - Lifetime EP1287818B1 (en) | 2001-08-31 | 2002-08-14 | Methods of antibiotic coating of objects having interconnected microcavities and the uses thereof |
Country Status (29)
Country | Link |
---|---|
US (1) | US6984410B2 (en) |
EP (1) | EP1287818B1 (en) |
JP (1) | JP3740449B2 (en) |
CN (1) | CN1203903C (en) |
AU (1) | AU2002300656B2 (en) |
BG (1) | BG65774B1 (en) |
BR (1) | BR0203427A (en) |
CA (1) | CA2396146C (en) |
CY (1) | CY1107271T1 (en) |
CZ (1) | CZ301740B6 (en) |
DE (1) | DE50211246D1 (en) |
DK (1) | DK1287818T3 (en) |
EE (1) | EE200200491A (en) |
ES (1) | ES2295268T3 (en) |
GE (1) | GEP20043333B (en) |
HR (1) | HRP20020680B1 (en) |
HU (1) | HUP0202916A3 (en) |
IL (1) | IL150999A0 (en) |
IS (1) | IS6390A (en) |
MD (1) | MD2633C2 (en) |
MX (1) | MXPA02008326A (en) |
NO (1) | NO20024101L (en) |
NZ (1) | NZ521043A (en) |
PL (1) | PL206972B1 (en) |
PT (1) | PT1287818E (en) |
RU (1) | RU2236261C2 (en) |
SA (1) | SA02230286B1 (en) |
SK (1) | SK9852002A3 (en) |
YU (1) | YU51902A (en) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10227935B4 (en) * | 2002-06-21 | 2007-10-04 | Heraeus Kulzer Gmbh | Process for the preparation of an antibiotic coating of porous bodies and use |
ITFI20030105A1 (en) * | 2003-04-14 | 2004-10-15 | Italmed Di Galli Giovanna E Pacini Gigliola S N C | COMPOSITION FOR DENTAL USE FOR BONE REGENERATION |
US20070134287A1 (en) * | 2005-12-09 | 2007-06-14 | Biomet Manufacturing Corp | Method for coating biocompatible substrates with antibiotics |
DE102006016598A1 (en) * | 2006-04-06 | 2007-11-15 | Heraeus Kulzer Gmbh | Coated vascular implants |
JP5161452B2 (en) | 2006-10-03 | 2013-03-13 | 日本コヴィディエン株式会社 | Method for manufacturing medical device, method for applying antibiotic to surface of medical device, and medical device |
CN101721750B (en) * | 2009-12-25 | 2013-08-07 | 安徽医科大学 | Method for preparing repairing material of antibacterial degradable active nanometer composite bionic tone tissue |
DE102010055560B4 (en) | 2010-12-23 | 2017-02-23 | Heraeus Medical Gmbh | coater |
DE102012002209A1 (en) * | 2012-02-07 | 2013-08-08 | Carl Freudenberg Kg | Biodegradable nonwoven for medical purposes |
WO2018059670A1 (en) | 2016-09-27 | 2018-04-05 | Wacker Chemie Ag | Process for producing spherical polysilsesquioxane particles |
EP3377559B1 (en) | 2016-10-06 | 2020-06-17 | Wacker Chemie AG | Method for producing spherical polysilsesquioxane particles |
US11517650B2 (en) | 2017-10-24 | 2022-12-06 | University Of Cincinnati | Antibiotic implant coatings and process for manufacturing implant coatings |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
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CA950831A (en) | 1972-04-25 | 1974-07-09 | Leonard D. Kurtz | Biocidal salts |
FR2272680B1 (en) * | 1974-05-29 | 1978-07-21 | Hosbon Sa Lab | |
DE2807132C2 (en) * | 1978-02-20 | 1983-11-03 | Battelle-Institut E.V., 6000 Frankfurt | Implantable pharmaceutical depot |
DE3206725A1 (en) | 1981-05-13 | 1982-12-02 | Merck Patent Gmbh, 6100 Darmstadt | PERSONALLY SOLUBLE SALTS OF AMINOGLYCOSIDANTIBIOTICS |
DE3206726A1 (en) | 1982-02-25 | 1983-09-01 | Merck Patent Gmbh, 6100 Darmstadt | PHARMACADEPOT |
DE4314871A1 (en) * | 1993-05-05 | 1994-11-10 | Merck Patent Gmbh | Solvent for a sparingly soluble gentamicin salt |
DE4404018A1 (en) | 1994-02-09 | 1995-08-10 | Merck Patent Gmbh | Protected release dosage forms containing clindamycin palmitate |
US5624704A (en) * | 1995-04-24 | 1997-04-29 | Baylor College Of Medicine | Antimicrobial impregnated catheters and other medical implants and method for impregnating catheters and other medical implants with an antimicrobial agent |
AU2676397A (en) | 1996-04-18 | 1997-11-07 | University Technology Corporation | Methods for treating middle and inner ear disorders |
US6417293B1 (en) * | 2000-12-04 | 2002-07-09 | Dow Corning Corporation | Thermoplastic silicone elastomers formed from polyester resins |
DE10114245A1 (en) * | 2001-03-22 | 2002-10-02 | Heraeus Kulzer Gmbh & Co Kg | Production and use of an antibiotic / antibiotic preparation |
-
2002
- 2002-05-17 IS IS6390A patent/IS6390A/en unknown
- 2002-06-03 MD MDA20020153A patent/MD2633C2/en not_active IP Right Cessation
- 2002-06-27 BG BG106881A patent/BG65774B1/en unknown
- 2002-07-02 CZ CZ20022322A patent/CZ301740B6/en not_active IP Right Cessation
- 2002-07-04 SK SK985-2002A patent/SK9852002A3/en unknown
- 2002-07-05 YU YUP51902 patent/YU51902A/en unknown
- 2002-07-29 CA CA 2396146 patent/CA2396146C/en not_active Expired - Fee Related
- 2002-07-31 IL IL15099902A patent/IL150999A0/en not_active IP Right Cessation
- 2002-08-12 GE GEAP2002004867 patent/GEP20043333B/en unknown
- 2002-08-13 US US10/217,788 patent/US6984410B2/en not_active Expired - Fee Related
- 2002-08-14 EP EP20020018322 patent/EP1287818B1/en not_active Expired - Lifetime
- 2002-08-14 PT PT02018322T patent/PT1287818E/en unknown
- 2002-08-14 DE DE50211246T patent/DE50211246D1/en not_active Expired - Lifetime
- 2002-08-14 ES ES02018322T patent/ES2295268T3/en not_active Expired - Lifetime
- 2002-08-14 DK DK02018322T patent/DK1287818T3/en active
- 2002-08-19 AU AU2002300656A patent/AU2002300656B2/en not_active Ceased
- 2002-08-20 HR HR20020680A patent/HRP20020680B1/en not_active IP Right Cessation
- 2002-08-27 MX MXPA02008326A patent/MXPA02008326A/en active IP Right Grant
- 2002-08-27 NZ NZ521043A patent/NZ521043A/en not_active IP Right Cessation
- 2002-08-28 JP JP2002249580A patent/JP3740449B2/en not_active Expired - Fee Related
- 2002-08-28 NO NO20024101A patent/NO20024101L/en not_active Application Discontinuation
- 2002-08-28 BR BR0203427A patent/BR0203427A/en not_active IP Right Cessation
- 2002-08-29 PL PL355778A patent/PL206972B1/en not_active IP Right Cessation
- 2002-08-30 EE EEP200200491A patent/EE200200491A/en unknown
- 2002-08-30 RU RU2002123420A patent/RU2236261C2/en not_active IP Right Cessation
- 2002-08-30 CN CNB02141503XA patent/CN1203903C/en not_active Expired - Fee Related
- 2002-08-30 HU HU0202916A patent/HUP0202916A3/en unknown
- 2002-09-03 SA SA02230286A patent/SA02230286B1/en unknown
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2008
- 2008-01-18 CY CY081100074T patent/CY1107271T1/en unknown
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